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| United States Patent |
5,164,391
|
|
Kurono
, et al.
|
*
November 17, 1992
|
Hydantoin derivatives for treating complications of diabetes and
circulatory diseases
Abstract
The invention relates to a hydantoin derivative, salt thereof, process for
the preparation thereof, and medicine containing the derivative. The
derivative is represented by the formula
##STR1##
wherein M is --CONH--NHR.sup.1 group, --CONH--OR.sup.2 group,
##STR2##
in which R.sup.1 is hydrogen atom, an alkyl group, an alkenyl group, a
phenyl radical, a substituted phenyl group, a naphthyl radical, a
substituted naphthyl group, a pyridyl radical, a furyl radical or a
thienyl radical, R.sup.2 is a hydrogen atom, an alkyl group, a phenyl
radical or a substituted phenyl group, R.sup.3 and R.sup.4 are the same or
different independently, each being a phenyl radical, or an aralkyl group,
or R.sup.3 may form a substituted or non-substituted C.sub.5-6 saturated
heterocyclic ring together with R.sup.4 and a possible nitrogen or oxygen
atom, R.sup.5 forms a substituted or non-substituted saturated
heterocyclic ring together with R.sup.6 and a possible nitrogen or oxygen
atom, R.sup.7 is a nitroxy radical or a heteroaryl group, .sub.m and
.sub.n are an integer of 2 to 5, Q is a hydrogen atom or
##STR3##
in which R.sup.8 and R.sup.9 are the same or different independently, each
being a substituted or non-substituted alkyl group, or R.sup.8 may form a
substituted or non-substituted C.sub.5-6 saturated heterocyclic ring
together with R.sup.9 and a possible nitrogen or oxygen atom, .sub.r is an
integer of 2 to 5, T and X are the same or different independently, each
being a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group or
an alkylmercapto group, and Z is an oxygen or sulfur atom.
The derivatives and salts thereof are useful for the treatment of
complications of diabetes and circulatory diseases.
| Inventors:
|
Kurono; Masayasu (Aichi, JP);
Unno; Ryoichi (Aichi, JP);
Kimura; Hiromoto (Aichi, JP);
Tomiya; Noboru (Aichi, JP);
Sawai; Kiichi (Aichi, JP);
Miura; Kenji (Aichi, JP);
Usui; Toshinao (Aichi, JP);
Kondo; Yasuaki (Aichi, JP);
Tanaka; Yukiya (Aichi, JP);
Nakamura; Shigeyoshi (Aichi, JP);
Suzuki; Tsunemasa (Aichi, JP);
Hayashi; Motohide (Aichi, JP)
|
| Assignee:
|
Sanwa Kagaku Kenkyusho Co., Ltd. (JP)
|
| [*] Notice: |
The portion of the term of this patent subsequent to April 26, 2005
has been disclaimed. |
| Appl. No.:
|
582039 |
| Filed:
|
September 13, 1990 |
Foreign Application Priority Data
| Sep 20, 1989[JP] | 1-242301 |
| Apr 27, 1990[JP] | 2-110136 |
| Apr 27, 1990[JP] | 2-110137 |
| Current U.S. Class: |
514/254.07; 514/232.5; 514/233.5; 514/317; 514/318; 514/320; 514/324; 514/389; 544/70; 544/230; 546/15; 548/301.1 |
| Intern'l Class: |
C07D 491/107; A61K 031/495; A61K 031/415; A61K 031/445 |
| Field of Search: |
548/309
544/70,230
546/15
514/233.5,253,320,324,389
|
References Cited
U.S. Patent Documents
| 4740517 | Apr., 1988 | Kurono et al. | 546/15.
|
| 4780472 | Oct., 1988 | Ueda et al. | 548/309.
|
| 4861792 | Aug., 1989 | Kurono et al. | 546/15.
|
| 4978758 | Dec., 1990 | Kurono et al. | 548/309.
|
Other References
Kurono et al., Chemical Abstracts, vol. 106, No. 5042 (1987) (Abstract for
EP 193415, Sep. 3, 1986).
Kinoshita et al.,, Jap. J. Ophthalmol. vol. 20: 399-410, 1976.
Gabbay, Int. Congr. Ser. Excerpta Med., 403,594 (1977).
Peterson et al., Metalbolism, vol. 28, No. 4, Suppl. 1 (Apr.), 1979.
Taguma et al., New England Journal of Medicine, vol. 313, No. 26, 1617,
1985.
Parying et al., British Medical Journal, vol. 294: 1443, 1987.
|
Primary Examiner: Shah; Mukund J.
Assistant Examiner: Bernhardt; E.
Attorney, Agent or Firm: Nikaido, Marmelstein, Murray & Oram
Claims
What is claimed is:
1. A hydantoin derivative selected from the group consisting of
a)
(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbohydra
zide,
b)
(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-(N'-methyl
)carbohydrazide,
c)
(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-(N'-phenyl
)carbohydrazide,
d)
(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-(N'-4-chlo
rophenyl)carbohydrazide,
e)
(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-(N'-4-meth
oxyphenyl)carbohydrazide,
f)
(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-(N'-1-naph
thyl)carbohydrazide,
g)
(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-hydroxamic
acid,
h)
(2S,4S)-N-[2-(4-cinnamylpiperazin-1-yl)ethyl]-6-fluoro-2',5'-dioxospiro[ch
roman-4,4'-imidazolidine]-2-carboxamide,
i)
(2S,4S)-N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-6-fluoro-2',5'-diox
ospiro[chroman-4,4'-imidazolidine]-2-carboxamide,
j)
(2S,4S)-N-{2-[4-(diphenylmethyl)piperazin-1-yl]ethyl}-6-fluoro-2',5'-dioxo
spiro[chroman-4,4'-imidazolidine]-2-carboxamide,
k)
(2S,4S)-N-[2-(4-benzylpiperadin-1-yl)ethyl]-6-fluoro-2',5-dioxospiro[chrom
an-4,4'-imidazolidine]-2-carboxamide,
l)
(2S,4S)-N-{2-[4-(3,4,5-trimethoxycinnamoylpiperozin-1-yl]ethyl}-6-fluoro-2
',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxamide,
m)
(2S,4S)-N-(2-nitroxyethyl)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazol
idine]-2-carboxamide,
n)
(2S,4S)-N-{2-[(imidazol-1-yl)ethyl]}-6-fluoro-2',5'-dioxospiro[chroman-4,4
'-imidazolidine]-2-carboxamide,
o)
(2S,4S)-1'-[3-(4-hydroxypiperidin-1-yl)propyl]-6-fluoro-2',5'-dioxospiro[c
hroman-4,4'-imidazolidine]-2-carboxamide,
p)
(2S,4S)-N-ethyl-1'-[3-(4-hydroxypiperidin-1-yl)propyl]-6-fluoro-2',5'-diox
ospiro[chroman-4,4'-imidazolidine]-2-carboxamide, and
q)
(2S,4S)-N-butyl-1'-[3-(4-hydroxypiperidin-1-yl)propyl]-6-fluoro-2',5'-diox
ospiro[chroman-4,4'-imidazolidine]-2-carboxamide.
2. A composition for treating circulatory diseases, complications of
diabetes, or both, which comprises an effective amount of a hydantoin
derivative selected from the group consisting of
a)
(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbohydra
zide,
b)
(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-(N'-methyl
)carbohydrazide,
c)
(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-(N'-phenyl
)carbohydrazide,
d)
(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-(N'-4-chlo
rophenyl)carbohydrazide,
e)
(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-(N'-4-meth
oxyphenyl)carbohydrazide,
f)
(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-(N'-1-naph
thyl)carbohydrazide,
g)
(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-hydroxamic
acid,
h)
(2S,4S)-N-[2-(4-cinnamylpiperazin-1-yl)ethyl]-6-fluoro-2',5'-dioxospiro[ch
roman-4,4'-imidazolidine]-2-carboxamide,
i)
(2S,4S)-N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-6-fluoro-2',5'-diox
ospiro[chroman-4,4'-imidazolidine]-2-carboxamide,
j)
(2S,4S)-N-{2-[4-(2-diphenylmethyl)piperazin-1-yl]ethyl}-6-fluoro-2',5'-dio
xospiro[chroman-4,4'-imidazolidine]-2-carboxamide,
k)
(2S,4S)-N-[2-(4-benzylpiperadin-1-yl)ethyl]-6-fluoro-2',5'-dioxospiro[chro
man-4,4'-imidazolidine]-2-carboxamide,
l)
(2S,4S)-N-{2-[4-(3,4,5-trimethoxycinnamoyl-piperazin-1-yl]ethyl}-6-fluoro-
2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxamide,
m)
(2S,4S)-N-(2-nitroxyethyl)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazol
idine]-2-carboxamide,
n)
(2S,4S)-N-{2-[(imidazol-1-yl)ethyl]}-6-fluoro-2',5'-dioxospiro[chroman-4,4
'-imidazolidine]-2-carboxamide,
o)
(2S,4S)-1'-[3-(4-hydroxypiperidin-1-yl)propyl]-6-fluoro-2',5'-dioxospiro[c
hroman-4,4'-imidazolidine]-2-carboxamide,
p)
(2S,4S)-N-ethyl-1'-[3-(4-hydroxypiperidin-1-yl)propyl]-6-fluoro-2',5'-diox
ospiro[chroman-4,4'-imidazolidine]-2-carboxamide, and
q)
(2S,4S)-N-butyl-1'-[3-(4-hydroxypiperidin-1-yl)propyl]-6-fluoro-2',5'-diox
ospiro[chroman-4,4'-imidazolidine]-2-carboxamide.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel hydantoin derivatives, salts
thereof, a process for the preparation thereof and a medicine comprising
at least one of the derivatives or the salts as an effective ingredient to
treat complications of diabetes and/or to prevent or cure circulatory
diseases.
2. Related Arts
Hitherto, various studies have been made to find out an effective compound
for curing diabetes, which compound can be formulated into a medicine for
oral dosage. As a result, various drugs, each of which comprises as an
effective ingredient, sulfonyl urea, mesooxalate, a guanidine derivative
or the like have been developed and marketed for clinical use, but those
are mere symptomatic treating agents to a hyperglycoplasmia due to the
diabetes. It has been known there may be caused due to the diabetes
specific chronic complications such as diabetic cataract, diabetic
neuropathy, diabetic retinopathy and the like, but there is almost no
effective agent for curing the complications and it may be said that no
effective therapeutic system has been established.
Therefore, hitherto, various studies have also been made for developing an
effective compound for curing such intractable diseases due to the
diabetes but it is the fact that there has been is almost no success case.
As one of studies for developing a compound for curing the complications
of diabetes, there is a search on an anti- or inhibition substance to
enzyme of aldose reductase, since the enzyme reduces in vivo of human
being, and other animals, aldoses such as glucose and galactose into
corresponding polyols such as sorbitol and galactitol and it has been
known that the complications will appear when the formed sorbitol and
galactitol are accumulated at crystalline lens, peripheral nerve, kidney
or the like tissue or organ in patients with the diabetes or galactosemia
["Jap. J. Opthamol.", Vol. 20, page 399 (1976); Int. Congr. Ser. Excepta
Med.", pages 403 and 594 (1977); and "Metabolism", Vol. 28, page 456
(1979)].
Some of the inventors and researchers in the assignee company have also
studied and investigated substances showing the inhibition to aldose
reductase to find out various hydantoin derivatives [Jap. Pat. Sho
61-200991(A) corresponding to U.S. Pat. No. 4,740,517 and EP 0193415(A2);
and Jap. Pat. Nos. Sho 61-199924(A) and 61-126881(A) corresponding to U.S.
Pat. No. 4,861,792 and EP 0264586(A1)].
Further, it has been known that there is a close relation between diabetes
and circulatory diseases, since the arteriosclerosis is the complications
of diabetes, which is caused with the highest frequency in occurrence and
one of causes thereof lies in metabolic abnormality of lipids due to the
diabetes. Moreover, a patient with a diabetic nephropathy has been often
complicated with a circulatory disease of a hypertonia. In connection with
this, such a report has been issued that a reduction in renal function of
patients with diabetes can be delayed by carrying out a treatment for
circulatory diseases and more particularly by dosing a hypotensor ["Br.
Mrd. J.", Vol. 294, page 1443 (1987) and "N. Eng. J. Med.", Vol. 313, page
1617 (1985)].
SUMMARY OF THE INVENTION
A primary object of the invention is to provide novel hydantoin derivatives
other than those having been developed by the parties belonging to the
assignee company discussed above, each of which shows an inhibition to the
enzyme of aldose reductase, thereby inhibiting an accumulation of
sorbitol, galactitol and the like polyols in a living body, to affect the
prevention and/or curing of intractable complications of diabetes
possible.
A secondary object of the invention is to provide novel hydantoin
derivatives with a low toxicity, and thus having excellent safety of use.
A tertiary but important object of the invention is to provide novel
hydantoin derivatives which also shown an action to the circulatory system
(depressing action of blood pressure), in addition to the inhibition to
aldose reductase, so that the accumulation of polyols in a living body and
occurrence of circulatory disease can be concurrently inhibited, to make
concurrent curing of the complications of diabetes and circulatory
diseases possible.
According to the invention, the objects can basically be attained by a
hydantoin derivative of the formula
##STR4##
wherein M is --CONH--NHR.sup.1 group, --CONH--OR.sup.2 group,
##STR5##
in which R.sup.1 is hydrogen atom, an alkyl group, an alkenyl group, a
phenyl radical, a substituted phenyl group, a naphthyl radical, a
substituted naphthyl group, a pyridyl radical, a furyl radical or a
thienyl radical, R.sup.2 is a hydrogen atom, an alkyl group, a phenyl
radical or a substituted phenyl group, R.sup.3 and R.sup.4 are the same or
different independently, each being a hydrogen atom, an alkyl group, a
phenyl radical, a substituted phenyl group or an aralkyl group, or R.sup.3
may form a substituted or non-substituted C.sub.5-6 saturated heterocyclic
ring together with R.sup.4 and a possible nitrogen or oxygen atom, R.sup.5
forms a substituted or non-substituted saturated heterocyclic ring
together with R.sup.6 and a possible nitrogen or oxygen atom, R.sup.7 is a
nitroxy radical or a heteroaryl group, .sub.n and .sub.m are an integer of
2 to 5, Q is a hydrogen atom or
##STR6##
in which R.sup.8 and R.sup.9 are the same or different independently, each
being a substituted or non-substituted alkyl group, or R.sup.8 may form a
substituted or non-substituted C.sub.5-6 saturated heterocyclic ring
together with R.sup.9 and a possible nitrogen or oxygen atom, .sub.r is an
integer of 2 to 5, T and X are the same or different independently, each
being a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group or
an alkylmercapto group, and Z is an oxygen or sulfur atom, or a
pharmaceutically acceptable salt thereof.
Namely, it has been confirmed that derivatives (I) show an effective
inhibition to aldose reductase, acts to the circulatory system and has a
quite low toxicity.
In derivatives (I), the alkyl group may be straight-chain alkyl radicals,
branched-chain alkyl radicals or cycloalkyl radicals. As examples for the
straight-chain alkyl radicals, one having 1 to 10 carbon atoms, for
instance methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl or the like
may be listed. As the branched-chain alkyl radicals, isopropyl, isobutyl,
s-butyl, t-butyl and the like may be listed. As the cycloalkyl radicals,
one having three or more carbon atoms, for instance cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and the like may be listed. As the
alkenyl group, for instance, allyl and the like may be listed. As the
substituent for substituted phenyl or naphthyl, fluorine, chlorine,
bromine and the like halogen atom, as well as methoxy, ethoxy and the like
alkoxy group may be listed. The number of the substituent may be of more
than one. As examples for the
##STR7##
wherein the substituents R.sup.3 and R.sup.4 represent together a
heterocyclic ring which may include a nitrogen or oxygen atom therein,
pyrrolidino, morpholino, piperidino, piperazino and the like may be
listed. As examples for the
##STR8##
wherein the substituents R.sup.5 and R.sup.6 represent together a
substituted or non-substituted saturated heterocyclic ring which may
include a nitrogen or oxygen atom therein, pyrrolidino, piperidino,
piperazino, morpholino and the like may be listed. As the heteroaryl
group, imidazolyl and the like may be listed. As examples for the
##STR9##
wherein the substituents R.sup.8 and R.sup.9 represent together a
heterocyclic ring which may include a nitrogen or oxygen atom therein,
pyrrolidino, morpholino, piperidino, piperazino and the like may be
listed. As the halogen atom, fluorine, chlorine and iodine may be listed,
but fluorine is preferable. As examples for the alkoxy group, those having
a straight-chain alkyl radical, for instance methoxy, ethoxy, n-propoxy,
n-butoxy, n-pentyloxy, n-hexyloxy and the like, as well as those having a
branched-chain alkyl radical, for instance isopropoxy, isobutoxy,
s-butoxy, t-butoxy and the like may be listed. As examples for the
alkylmercapto group, those having a straight-chain alkyl radical, for
instance, methylmercapto, ethylmercapto, n-propylmercapto,
n-butylmercapto, n-pentylmercapto, n-hexylmercapto and the like, as well
as those having a branched-chain alkyl radical, for instance
isopropylmercapto, isobutylmercapto, s-butylmercapto, t-butylmercapto and
the like may be listed.
In the specification, the salt of derivatives (I) means those acceptable
for employing the same as an effective ingredient for a medicine. As
specific examples, those with an inorganic acid such as phosphoric acid,
hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid or the
like, an organic acid such as acetic acid, succinic acid, fumaric acid,
lactic acid, tartaric acid, citric acid, methanesulfonic acid or the like
may be listed.
Each of derivatives (I) according to the invention has two asymmetric
carbon atoms in its structure and thus has two kinds of stereo isomers and
optical isomers thereof. It should be noted that those are, of course,
included in scope of the invention.
The hydantoin derivatives (I) can be prepared as stated below.
Among the derivatives, the compound of the formula
##STR10##
wherein T and Z have the meanings as referred to, and M.sup.1 is
--CONH--NHR.sup.1 group or --CONH--OR.sup.2 group, in which R.sup.1 and
R.sup.2 have the meanings as referred to, can be prepared by reacting a
compound of the formula
##STR11##
wherein T and Z have the meanings as referred to, with a halogenizing or
esterifying reagent, and reacting the resulting compound of the formula
##STR12##
wherein T and Z have the meanings as referred to and A is chlorine atom,
methoxy radical or n-propoxy radical, with a compound of the formula
R.sup.1 --NHNH.sub.2 (IV) or
R.sup.2 --ONH.sub.2 (V)
wherein R.sup.1 and R.sup.2 have the meanings as referred to.
The compounds II and III may be prepared according to the process as
disclosed in Jap. Pat. Nos. Sho 63-57588(A) and 63-250373(A).
Among the derivatives, the compound of the formula
##STR13##
wherein T, X and Z have the meanings as referred to, and M.sup.2 is
##STR14##
in which R.sup.5, R.sup.6, R.sup.7, .sub.m and .sub.n have the meanings as
referred to, can be prepared by reacting a compound of the formula
##STR15##
wherein T, X and Z have the meanings as referred to, and M' is an active
carbonyl radical, with a compound of the formula
##STR16##
wherein R.sup.5, R.sup.6 and .sub.m have the meanings as referred to, or a
compound of the formula
H.sub.2 N(CH.sub.2).sub.n R.sup.7
wherein R.sup.7 and .sub.n have the meanings as referred to.
The starting compound (VI) may be prepared according to the process as
disclosed in Jap. Pat. No. Sho 63-57588(A). The reaction can be carried
out by stirring the reactants under room temperature to reflux
temperature, in the presence of an inert solvent. As the inert solvent,
dimethylformamide, dimethylsulfoxide dimethylacetamide, dioxane,
tetrahydrofuran and the like can be listed.
Among the derivatives (I), the compound of the formula
##STR17##
wherein T, X and Z have the meanings as referred to, and M.sup.3 is
##STR18##
and Q' is
##STR19##
in which R.sup.3, R.sup.4, R.sup.8, R.sup.9 and .sub.r have the meanings
as referred to, can be prepared by reacting the compound of the formula
##STR20##
wherein M.sup.3, T, X and Z have the meanings as referred to, with a
compound of the formula
Hal(CH.sub.2).sub.r NR.sup.8 R.sup.9
wherein R.sup.8, R.sup.9, and .sub.r have the meanings as referred to, and
Hal is a halogen atom, or reacting compound (VII) with a compound
Hal--(CH.sub.2).sub.r --Hal
wherein Hal and .sub.r have the meanings as referred to, and then the
resulting compound of the formula
##STR21##
wherein M.sup.3, T, X, Z and Hal have the meanings as referred to, with a
compound of the formula
HNR.sup.8 R.sup.9
wherein R.sup.8 and R.sup.9 have the meanings as referred to.
The reaction can be carried out by reacting compound (VII) with a base,
e.g. sodium hydride, potassium hydride or the like, at temperature of
ice-cooling to room temperature and in the presence of a solvent, and
adding the other reactant to cause the reaction at temperature of room
temperature to reflux temperature. As the solvent, dimethylformamide,
dimethylsulfoxide, dimethylacetamide, dioxane, tetrahydrofuran or the like
may be used.
There is no specific limitation, when the derivative or salt according to
the invention will be made into a medicine containing at least one of the
compounds or salts, as effective ingredient. Therefore, the medicine may
be of a solid form such as tablet, pill, capsule, powder, granule and
suppository, or a liquid form of solution, suspension or emulsion,
together with a conventional additive(s) and/or a carrier(s). The medicine
of such a form can be prepared in a conventional manner. For preparing the
medicine in a solid form, starch, lactose, glucose, calcium phosphate,
magnesium stearate, gum arabic or the like vehicle may be used, and if
necessary a lublicant, binder, disintegrating agent, coloring agent,
flavour and the like may be added. For preparing the medicine of liquid
form, a stabilizer, an assistance for dissolving, suspendizer, emulsifier,
buffer, reserving agent or the like may be used.
A dosing amount of the derivative or salt for human being depends on the
selected compound or salt per se, the condition of illness, the age of the
patient, the form of the medicine and other factors, but in case of an
adult, 0.1 to 3000 mg/day and more particularly 1 to 300 mg/day are
preferable.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The invention will now be further explained in more detail with reference
to Manufacturing Examples, Pharmacological Test Examples as well as
Prescription Examples.
EXAMPLE 1
(2S,4S)-6-Fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbohydraz
ide
To a solution of
(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxylic
acid n-propyl ester (30.0 g, 93.1 mmol) in 600 ml of ethanol was added
hydrazine hydrate (46.6 g, 0.931 mol). After refluxing the mixture under
an argon atmosphere for 2 hours, the reaction mixture was evaporated in
vacuo to dryness. To the residue was added 100 ml of saturated aqueous
sodium chloride and the aqueous layer was extracted with ethyl acetate
(300 ml.times.5). The combined ethyl acetate layers were washed with
water, dried over anhydrous sodium sulfate, filtered and evaporated in
vacuo to give 17.3 g (Yield: 63.1%) of crude crystals. The crystals were
recrystallized from ethanol to give colorless needles of the desired
compound (12.8 g, 46.7%).
Melting point: 277.degree.-278.degree. C.
[.alpha.].sub.D.sup.25 : +139.degree. (c=1.0, methanol).
IR spectrum (v.sub.max.sup.KBr) cm.sup.-1 : 3450, 3330, 3060, 1775, 1725,
1660.
NMR spectrum (DMSO-d.sub.6) .delta. ppm:
______________________________________
2.13 (1H, dd, J= 14.2 and 12.4Hz),
2.40 (1H, dd, J= 14.2 and 2.4Hz),
4.39 (2H, s),
5.10 (1H, dd, J= 12.4 and 2.4Hz),
6.9-7.2 (3H, m),
8.38 (1H, s),
9.59 (1H, s),
11.00 (1H, s).
______________________________________
Mass spectrum (EI/DI) m/z: 294 (M.sup.+, base peak), 235, 192.
EXAMPLE 2
(2S,4S)-6-Fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-(N'-methyl)
carbohydrazide
To a solution of
(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxylic
acid n-propyl ester (30.0 g, 93.1 mmol) in 800 ml of n-propanol was added
methylhydrazine (44.2 g, 0.931 mol). After refluxing the mixture under an
argon atmosphere for 18 hours, the reaction mixture was concentrated to
half volume and a formed precipitate was removed by filtration. The
filtrate was evapolated in vacuo to dryness and to the residue was added
100 ml of water. The resulting crystals were obtained through a filtration
and dried in vacuo to give colorless crystals of the desired compound
(20.3 g, 70.9%).
Melting point: 276.degree.-278.degree. C.
[.alpha.].sub.D.sup.25 : +137.degree. (c=1.0, methanol).
IR spectrum (v.sub.max.sup.KBr) cm.sup.-1 : 3430, 3060, 1775, 1730, 1660.
NMR spectrum (DMSO-d.sub.6) .delta. ppm:
______________________________________
2.12 (1H, dd, J= 13.7 and 12.7Hz),
2.41 (1H, dd, J= 13.7 and 2.4Hz),
2.47 (3H, s),
4.97 (1H, brs),
5.09 (1H, dd, J= 12.2 and 2.4Hz),
6.9-7.2 (3H, m),
8.39 (1H, s),
9.85 (1H, s),
11.02 (1H, s).
______________________________________
Mass spectrum (EI/DI) m/z: 308 (M.sup.+), 278, 235, 192 (base peak).
EXAMPLE 3
(2S,4S)-6-Fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-(N'-phenyl)
carbohydrazide
To thionyl chloride (24.9 ml, 3.57 mol) was added
(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxylic
acid (20.0 g, 71.4 mmol). After refluxing the mixture under argon
atmosphere for 22 hours, the excess thionyl chloride was evaporated in
vacuo to dryness to give quantitatively crude crystals of
(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl
chloride.
To a solution of this acid chloride in 200 ml of N,N-dimethylformamide were
added phenylhydrazine (15.6 g, 0.143 mol) and triethylamine (14.4 g, 0.143
mol). After stirring the mixture at 25.degree. C. for 18 hours, 600 ml of
water was added to the reaction mixture. The resulting mixture was
extracted with ethyl acetate (400 ml.times.3). The combined ethyl acetate
layers were washed with water, dried over anhydrous sodium sulfate,
filtered and evaporated in vacuo to dryness. The resulting residue was
chromatographed on silica gel, eluted with a mixture of dichloromethane
and methanol (20:1) to give colorless crystals (21.3 g, 80.6%). The
crystals were recrystallized from 50% aqueous ethanol to give colorless
needles of the desired compound (17.4 g, 65.9%).
Melting point: 254.degree.-255.degree. C.
[.alpha.].sub.D.sup.25 : +130.degree. (c=1.0, methanol).
IR spectrum (v.sub.max.sup.KBr) cm.sup.-1 : 3520, 3400, 3060, 1775, 1735,
1670.
NMR spectrum (DMSO-d.sub.6) .delta. ppm:
______________________________________
2.19 (1H, dd, J= 13.7 and 12.2Hz),
2.52 (1H, dd, J= 13.7 and 2.4Hz),
5.20 (1H, dd, J= 12.2 and 2.4Hz),
6.7-6.8 (5H, m),
6.9-7.2 (3H, m),
7.84 (1H, s),
8.39 (1H, s),
10.25 (1H, s),
11.02 (1H, s).
______________________________________
Mass spectrum (EI/DI) m/z: 370 (M.sup.+), 307, 278, 235, 192 (base peak).
EXAMPLE 4
(2S,4S)-6-Fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-(N'-4-chlor
ophenyl)carbohydrazide
This compound was prepared by the same procedure as in the case of Example
3, except that 4-chlorophenylhydrazine (20.4 g, 0.143 mol) was employed
for phenylhydrazine to obtain the desired compound (21.7 g, 75.1%).
Melting point: 169.degree.-171.degree. C.
[.alpha.].sub.D.sup.25 : +121.degree. (c=1.0, methanol).
IR spectrum (v.sub.max.sup.KBr) cm.sup.-1 : 3510, 3400, 3060, 1775, 1735,
1670.
NMR spectrum (DMSO-d.sub.6) .delta. ppm:
______________________________________
2.19 (1H, dd, J= 13.7 and 12.2Hz),
2.50 (1H, dd, J= 13.7 and 2.4Hz),
5.26 (1H, dd, J= 12.2 and 2.4Hz),
6.9-7.2 (3H, m),
7.18 (2H, d, J= 8.8Hz),
8.00 (1H, s),
8.36 (1H, s),
10.27 (1H, s),
11.01 (1H, s).
______________________________________
Mass spectrum (EI/DI) m/z: 404 (M.sup.+), 192 (base peak).
EXAMPLE 5
(2S,4S)-6-Fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-(N'-4-metho
xyphenyl)carbohydrazide
This compound was prepared by the same procedure as in the case of Example
3, except that 4-methoxyphenylhydrazine (19.7 g, 0.143 mol) was employed
for phenylhydrazine to obtain the desired compound (22.3 g, 78.0%).
Melting point: 154.degree.-157.degree. C.
[.alpha.].sub.D.sup.25 : +127.degree. (c=1.0, methanol).
Ir spectrum (v .sub.max.sup.KBr) cm.sup.-1 : 3400, 3060, 1775, 1730, 1690.
NMR spectrum (DMSO-d.sub.6) .delta. ppm:
______________________________________
2.22 (1H, dd, J= 13.7 and 12.2Hz),
2.50 (1H, dd, J= 13.7 and 2.4Hz),
5.23 (1H, dd, J= 12.2 and 2.4Hz),
6.6-7.2 (7H, m),
7.51 (1H, d, J= 3.0Hz),
8.38 (1H, s),
10.22 (1H, d),
11.03 (1H, s).
______________________________________
Mass spectrum (EI/DI) m/z: 400 (M.sup.+), 137 (base peak).
EXAMPLE 6
(2S,4S)-6-Fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-(N'-1-napht
hyl)carbohydrazide
This compound was prepared by the same procedure as in the case of Example
3, except that 1-naphthylhydrazine hydrochloride (20.4 g, 0.143 mol) was
employed for phenylhydrazine to obtain the desired compound (22.7 g,
75.8%).
Melting point: 285.degree.-288.degree. C.
[.alpha.].sub.D.sup.25 : +131.degree. (c=1.0, methanol).
IR spectrum (v.sub.max.sup.KBr) cm.sup.-1 : 3370, 3330, 3060, 1780, 1735,
1680.
NMR spectrum (DMSO-d.sub.6) .delta. ppm:
______________________________________
2.27 (1H, dd, J= 13.7 and 12.2Hz),
2.55 (1H, dd, J= 13.7 and 2.4Hz),
5.36 (1H, dd, J= 12.2 and 2.4Hz),
6.7-8.2 (10H, m),
8.34 (1H, s),
8.38 (1H, s),
10.40 (1H, s),
11.03 (1H, s).
______________________________________
Mass spectrum (EI/DI) m/z: 420 (M.sup.+), 143 (base peak).
EXAMPLE 7
(2S,4S)-6-Fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-hydroxamic
acid
To a solution of sodium hydroxide (10.7 g, 0.248 mol) in 400 ml of methanol
were added hydroxylamine hydrochloride (13.3 g, 0.186 mol) in 200 ml of
methanol and
(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxylic
acid n-propyl ester (20.0 g, 62.1 mmol) in 400 ml of methanol. After
stirring the mixture at 25.degree. C. for 18 hours, the reaction mixture
was evaporated in vacuo to dryness. To the residue was added 200 ml of
water and the resulting solution was acidified with concentrated
hydrochloric acid and extracted with ethyl acetate (300 ml.times.4). The
combined organic layers were washed with 250 ml of saturated aqueous
sodium chloride, dried over anhydrous sodium sulfate, filtered and
evaporated in vacuo to give a pale yellow oil (16.8 g, 91.8%). The oil was
dissolved in 400 ml of water, treated with active carbon and lyophilized
to give a colorless powder of the desired compound (15.0 g, 82.0%).
Melting point: 178.degree. C.
[.alpha.].sub.D.sup.25 : +135.degree. (c=1.0, methanol).
IR spectrum (v.sub.max.sup.KBr) cm.sup.-1 : 3400, 3060, 1775, 1725, 1680.
NMR spectrum (DMSO-d.sub.6) .delta. ppm:
______________________________________
2.17 (1H, dd, J= 13.7 and 12.2Hz),
2.39 (1H, dd, J= 13.7 and 2.4Hz),
5.07 (1H, dd, J= 12.2 and 2.4Hz),
6.9-7.2 (3H, m),
8.39 (1H, s),
9.11 (1H, s),
11.02 (1H, s),
11.10 (1H, s).
______________________________________
Mass spectrum (EI/DI) m/z: 295 (M.sup.+), 279 (base peak), 235.
REFERENCE EXAMPLE 1
(2S,4S)-6-Fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl
chloride
To thionyl chloride (400 ml, 5.11 mol) was added
(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxylic
acid (20.0 g, 67.1 mmol). After refluxing the mixture for 18 hours, the
resulting reaction mixture was dried in vacuo to dryness to give the
desired compound (20.0 g, 100%).
In the following Examples, the resulting crude product was employed as it
was.
EXAMPLE 8
(2S,4S)-N-[2-(4-Cinnamylpiperazin-1-yl)ethyl]-6-fluoro-2',5'-dioxospiro[chr
oman-4,4'-imidazolidine]-2-carboxamide
To a chilled mixture (less than -5.degree. C.) of
4-(2-aminoethyl)-1-cinnamylpiperazine (10.0 g, 40.8 mmol),
1,8-diazabicyclo[5,4,0]-7-undecene (6.20 g, 40.8 mmol) and
N,N-dimethylformamide (55.0 ml, 710 mmol) was added over 30 minutes a
solution of
(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl
chloride (Reference Example 1, 11.1 g, 37.1 mmol) in N,N-dimethylformamide
(100.1 ml, 1.29 mol). After stirring the mixture for 15 hours at
25.degree. C., the solvent was evaporated. The residue was chromatographed
on silica gel, eluted with a mixture of AcOEtAcOEt/MeOH (9:1), and
evaporated in vacuo to dryness to give a colorless oil of the desired
compound (17.5 g, 92.6%).
Melting point: 133.degree.-135.degree. C.
IR spectrum (v.sub.max.sup.KBr) cm.sup.-1 : 3412, 2822, 1728, 1665, 1539,
1491.
NMR spectrum (DMSO-d.sub.6) .delta. ppm:
______________________________________
2.28-2.67
(14H, m),
3.16-3.60
(2H, m),
5.07-5.20
(1H, m),
6.27-6.41
(1H, m),
6.55-6.65
(1H, m),
7.00-7.55
(8H, m),
8.15-8.26
(1H, m),
8.41 (1H, s),
11.10 (1H, brs).
______________________________________
Mass spectrum (EI/DI) m/z: 507 (M.sup.+), 217 (base peak).
EXAMPLE 9
(2S,4S)-N-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl}-6-fluoro-2',5'-dioxo
spiro[chroman-4,4'-imidazolidine]-2-carboxamide
This compound was prepared by the similar procedure as in the case of
Example 8, excepting that 4-(2-aminoethyl)-1-(2-methoxyphenyl)pyperazine
and
(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl
chloride (Reference Example 1) were employed.
Yield: 76.9%.
Melting point: 163.degree.-195.degree. C.
IR spectrum (v.sub.max.sup.KBr) cm.sup.-1 : 3324, 2830, 1728, 1657, 1491,
1242.
NMR spectrum (DMSO-d.sub.6) .delta. ppm:
______________________________________
2.05-2.58
(6H, m),
2.95-2.96
(4H, m),
3.28-3.35
(4H, m),
3.77 (3H, s),
5.13-5.14
(1H, m),
6.85-7.19
(7H, m),
7.15-8.19
(1H, m),
8.35 (1H, s),
10.99 (1H, brs).
______________________________________
Mass spectrum (EI/DI) m/z: 497 (M.sup.+), 205 (base peak).
EXAMPLE 10
(2S,4S)-N-{2-[4-(2-Diphenylmethyl)piperazin-1-yl]ethyl}-6-fluoro-2',5'-diox
ospiro[chroman-4,4'-imidazolidine]-2-carboxamide
(a) 1-(2-Aminoethyl)-4-diphenylmethylpiperazine
A mixture of 1-diphenylmethylpiperazine (30.0 g, 119 mmol),
N-(2-bromoethyl)phthalimide (30.3 g, 119 mmol), K.sub.2 CO.sub.3 (16.5 g,
120 mmol) and N,N-dimethylformamide (90.0 ml, 1.16 mol) were stirred for
24 hours at 75.degree. C. After evaporated the solvent in vacuo, the
resulting residue was chromatographed on silica gel, eluted with CH.sub.2
Cl.sub.2 /MeOH (9/1), and evaporated in vacuo to dryness to give
2-(4-diphenylmethylpiperazin-1-yl)ethylphthalimide (18.1 g, 42.9%).
A mixture of this compound (18.0 g, 42.3 mmol), NH.sub.2 NH.sub.2.H.sub.2 O
(2.50 g, 50.0 mmol) and EtOH (400 ml) was refluxed for 3 hours, cooled and
filtered. The resulting filtrate was concentrated in vacuo,
chromatographed on silica gel, eluted with AcOEt/NEt.sub.3
(1/1)-AcOEt/NEt.sub.3 /MeOH (5/4/1), and evaporated in vacuo to dryness to
give the desired compound (10.6 g, 84.8%).
(b)
(2S,4S)-N-{2-[4-(Diphenylmethyl)piperazin-1-yl]ethyl}-6-fluoro-2',5'-dioxo
spiro[chroman-4,4'-imidazolidine]-2-carboxamide
A mixture of 1-(2-aminoethyl)-4-diphenylmethylpiperazine (10.0 g, 33.9
mmol), 1,8-diazabicyclo[5,4,0]-7-undecene (10.9 g, 71.7 mmol) and
N,N-dimethylformamide (90.0 ml, 1.16 mol) was chilled to -30.degree. C. To
the mixture was added over 30 minutes a solution of (2S,
4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl
chloride (Reference Example 1, 10.0 g, 33.5 mmol) in N,N-dimethylformamide
(90.0 ml, 1.16 mol) and the mixture was stirred for 15 hours at
temperature of 15.degree.-25.degree. C. After distilling off the solvent,
the reaction mixture was chromatographed on silica gel, eluted with
CH.sub.2 Cl.sub.2 /MeOH (9/1) and evaporated in vacuo to dryness to give
the desired compound (12.2 g, 65.2%) as colorless amorphous substance.
Melting point: 200.degree.-205.degree. C.
IR spectrum (v.sub.max.sup.KBr) cm.sup.-1 : 3400, 2810, 1780, 1730, 1665,
1490.
NMR spectrum (DMSO-d.sub.6) .delta. ppm:
______________________________________
2.07-3.73
(14H, m),
4.32 (1H, s),
5.11-5.16
(1H, m),
6.89-7.50
(13H, m),
8.24-8.29
(1H, m),
8.47 (1H, s),
11.12 (1H, brs).
______________________________________
Mass spectrum (EI/DI) m/z: 557 (M.sup.+), 167 (base peak).
EXAMPLE 11
(2S,4S)-N-[2-(4-Benzylpiperidin-1-yl)ethyl]-6-fluoro-2'5'-dioxospiro[chroma
n-4,4'-imidazolidine]-2-carboxamide
A mixture of N-(2-aminoethyl)-4-benzylpiperidine (13.0 g, 59.6 mmol),
1,8-diazabicyclo[5,4,0]-7-undecene (10.9 g, 71.7 mmol) and
N,N-dimethylformamide (90.0 ml, 1.16 mol) was chilled to -30.degree. C. To
the mixture was added over 30 minutes a solution of (2S,
4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl
chloride (Reference Example, 18.0 g, 60.3 mmol) in N,N-dimethylformamide
(90.0 ml, 1.16 mol) and the mixture was stirred for 15 hours at
temperature of 15.degree.-25.degree. C. After distilling off the solvent,
the reaction mixture was chromatographed on silica gel, eluted with
CH.sub.2 Cl.sub.2 /MeOH (9/1) and evaporated in vacuo to dryness to give
the desired compound (14.3 g, 50.0%) as colorless amorphous substance.
Melting point: 231.degree.-232.degree. C.
IR spectrum (v.sub.max.sup.KBr) cm.sup.-1 : 3230, 2925, 1785, 1725, 1655,
1490.
NMR spectrum (DMSO-d.sub.6) .delta. ppm:
______________________________________
1.15-2.70
(13H, m),
2.85-3.03
(2H, m),
3.29-3.44
(2H, m),
5.18-5.21
(1H, m),
7.09-7.43
(8H, m),
8.15-8.40
(1H, s),
8.52 (1H, s),
11.00 (1H, brs).
______________________________________
Mass spectrum (EI/DI) m/z: 480 (M.sup.+), 188 (base peak).
EXAMPLE 12
(2S,4S)-N-{2-[4-(3,4,5-Trimethoxycinnamoyl)piperazin-1-yl]ethyl}-6-fluoro-2
',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxamide
3,4,5-Trimethoxycinnamic acid was chlorinated with SOCl.sub.2 to convert
into 3,4,5-trimethoxycinnamoyl chloride which was reacted with piperazine,
in a 6 fold amount to synthesize 1-(3,4,5-trimethoxycinnamoyl)piperazine,
with a yield of 42.6%. Then, this compound was reacted in a conventional
manner with N-(2-bromoethyl)phthalimide to synthesize
N-{[2-(3,4,5-trimethoxycinnnamoypiperazin)-1-yl]ethyl}phthalimide with
yield of 55.0%. This compound and NH.sub.2 NH.sub.2.H.sub.2 O in
equi-amount were refluxed in a mixed solvent of MeOH/CHCl.sub.3 for 6
hours to synthesize
4-(2-aminoethyl)-1-(3,4,5-trimethoxycinnamoyl)piperazine with yield of
66.9%.
The procedure similar to that described in Example 8 was carried out with
the use of the compound of
4-(2-aminoethyl)-1-(3,4,5-trimethoxycinnamoyl)piperazine and
(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl
chloride (Reference Example 1) to give the desired compound with yield of
72.0%.
Melting point: <183.degree. C.
IR spectrum (v.sub.max.sup.KBr) cm.sup.-1 : 3400, 2940, 1780, 1730, 1645,
1490.
NMR spectrum (DMSO-d.sub.6) .delta. ppm:
______________________________________
2.14-2.65
(8H, m),
3.33-3.92
(6H, m),
3.85 (3H, s),
3.87 (6H, s),
5.24-5.28
(1H, m),
6.70-7.58
(8H, m).
______________________________________
Mass spectrum (EI/DI) m/z: 221 (base peak).
EXAMPLE 13
(2S,
4S)-N-(2-Nitroxyethyl)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidin
e]-2-carboxamide
The procedure similar to that as described in Example 8 was carried out
with use of 2-nitroxyethylamine and
(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl
chloride (Reference Example 1) to give the desired compound.
Yield: 82.3%.
Melting point: 266.degree.-271.degree. C.
IR spectrum (v.sub.max.sup.KBr) cm.sup.-1 : 3420, 1780, 1730, 1645, 1490,
1280.
NMR spectrum (DMSO-d.sub.6) .delta. ppm:
______________________________________
1.99-2.49
(2H, m),
3.44-3.53
(2H, m),
4.59 (2H, t, J= 5Hz),
5.07-5.13
(1H, m),
6.97-7.20
(3H, m),
8.40 (1H, s),
8.54-8.59
(1H, m),
11.03 (1H, s).
______________________________________
Mass spectrum (EI/DI) m/z: 305 (M.sup.+ -63), 114 (base peak).
EXAMPLE 14
(2S,4S)-N-{2-[(Imidazol-1-yl)ethyl]}-6-fluoro-2',5'-dioxospiro[chroman-4,4'
-imidazolidine]-2-carboxamide
The procedure similar to that as described in Example 8 was carried out
with use of 1-(2-aminoethyl)imidazole and
(2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl
chloride (Reference Example 1) to give the desired compound.
Yield: 72.6%.
Melting point: 151.degree.-153.degree. C.
IR spectrum (v.sub.max.sup.KBr) cm.sup.-1 : 3432, 1722, 1491, 1262, 1121.
NMR spectrum (DMSO-d.sub.6) .delta. ppm:
______________________________________
2.10-2.63
(2H, m),
3.50-3.70
(2H, m),
4.20-4.24
(2H, m),
5.17-5.22
(1H, m),
6.99 (1H, s),
7.07-7.30
(4H, m),
7.68 (1H, s),
8.49-8.52
(2H, m),
11.11 (1H, brs).
______________________________________
Mass spectrum (EI/DI) m/z: 373 (M.sup.+), 138 (base peak).
REFERENCE EXAMPLE 2
(2S,4S)-1'-(3-Chloropropyl)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazol
idine]-2-carboxamide
To a solution of
(2S,4S)-6-fluoro-4',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxamid
e (27.9 g, 100 mmol) in N,N-dimethylformamide (150 ml, 1.94 mmol) was added
1-bromo-3-chloropropane (31.5 g, 200 mmol). After adding 60% NaH (4.00 g,
100 mmol) over 30 minutes at 15.degree.-20.degree. C., the mixture was
stirred for 15 hours at 25.degree.-30.degree. C. The reaction mixture was
poured into iced water (500 ml), extracted with AcOEt (1000 ml.times.3),
dried over MgSO.sub.4. The solvent was distilled off, the residue was
chromatographed on silica gel, eluted with CH.sub.2 Cl.sub.2 -CH.sub.2
Cl.sub.2 /MeOH (5/1) to give the desired compound (28.8 g, 81.0%) as
colorless prism crystals.
Melting point: 174.degree.-176.degree. C.
Mass spectrum (EI/DI) m/z: 355 (M.sup.+, base peak).
EXAMPLE 15
(2S,4S)-1'-[3-(4-Hydroxypiperidin-1-yl)propyl]-6-fluoro-2',5'-dioxospiro[ch
roman-4,4'-imidazolidine]-2-carboxamide
A mixture of
(2S,4S)-1'-(3-chloropropyl)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazo
lidine]-2-carboxamide (Reference Example 2, 15.0 g, 42.2 mmol),
4-hydroxypiperidine (8.52 g, 84.4 mmol), K.sub.2 CO.sub.3 (7.00 g, 50.7
mmol) and N,N-dimethylformamide (100 ml, 1.29 mol) was stirred for 5 hours
at 80.degree. C. After distilling off the solvent, the residue was
chromatographed on silica gel, eluted with CH.sub.2 Cl.sub.2
/MeOH/NEt.sub.2 (5/1/1), and recrystallized from AcOEt/MeOH to give prism
crystals of the desired compound (16.2 g, 91.5%).
Melting point: 208.degree.-209.degree. C.
IR spectrum (v.sup.KBr.sub.max) cm.sup.-1 : 3500, 3380, 1780, 1725, 1495,
1120.
NMR spectrum (DMSO-d.sub.6) .delta. ppm:
______________________________________
1.28-2.67
(15H, m),
3.16-3.44
(2H, m),
4.48 (1H, m),
5.07-5.02
(1H, m),
7.20-6.89
(3H, m),
7.52 (1H, s),
7.75 (1H, s),
8.67 (1H, s).
______________________________________
Mass spectrum (EI/DI) m/z: 420 (M.sup.+), 114 (base peak).
REFERENCE EXAMPLE 3
(2S,4S)-N-Ethyl-1'-(3-chloropropyl)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-
imidazolidine]-2-carboxamide
To a solution of
(2S,4S)-N-ethyl-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-ca
rboxamide (21.0 g, 68.4 mmol) in N,N-dimethylformamide (100 ml, 1.29 mmol)
was added 1-bromo-3-chloropropane (21.5 g, 137 mmol). After adding 60% NaH
(2.75 g, 68.8 mmol) over 30 minutes at 15.degree.-20.degree. C., the
mixture was stirred for 15 hours at 15.degree.-25.degree. C. The reaction
mixture was poured into iced water (500 ml), extracted with AcOEt (1000
ml.times.3), dried over MgSO.sub.4. The solvent was distilled off, the
residue was chromatographed on silica gel, eluted with CH.sub.2 Cl.sub.2
-CH.sub.2 Cl.sub.2 /MeOH (9/1), and recrystallized from AcOEt to give the
desired compound (19.3 g, 73.8%) as colorless prism crystals.
Melting point: 95.degree.-97.degree. C.
Mass spectrum (EI/DI) m/z: 383 (M.sup.+, base peak).
EXAMPLE 16
(2S,4S)-N-Ethyl-1'-[3-(4-hydroxypiperidin-1-yl)propyl]-6-fluoro-2',5'-dioxo
spiro[chroman-4,4'-imidaxolidine]-2-carboxamide
A mixture of
(2S,4S)-N-ethyl-1'-(3-chloropropyl)-6-fluoro-2',5'-dioxospiro[chroman-4,4'
-imidazolidine]-2-carboxamide (Reference Example 3, 18.0 g, 46.9 mmol),
4-hydroxypiperidine (9.47 g, 93.8 mmol), K.sub.2 CO.sub.3 (7.77 g, 56.3
mmol) and N,N-dimethylformamide (90.0 ml, 1.17 mol) was stirred for 5.5
hours at 80.degree.-85.degree. C. After distilling off the solvent, the
residue was chromatographed on silica gel, eluted with CH.sub.2 Cl.sub.2
/MeOH (9/1), and evaporated in vacuo to dryness to give amorphous crystals
of the desired compound (17.8 g, 84.8%).
Melting point: 98.degree.-100.degree. C.
IR spectrum (v.sub.max.sup.KBr) cm.sup.-1 : 3430, 1775, 1720, 1715, 1495.
NMR spectrum (DMSO-d.sub.6) .delta. ppm:
______________________________________
1.13 (3H, t, J= 7Hz),
1.36-2.28
(17H, m),
3.19-3.55
(2H, m),
4.58 (1H, m),
5.12-5.18
(1H, m),
7.28-6.97
(3H, m),
8.41 (1H, m),
8.75 (1H, s).
______________________________________
Mass spectrum (EI/DI) m/z: 448 (M.sup.+), 114 (base peak).
REFERENCE EXAMPLE 4
(2S,4S)-N-Butyl-1'-(3-chloropropyl)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-
imidazolidine]-2-carboxamide
To a solution of
(2S,4S)-N-butyl-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-ca
rboxamide (25.0 g, 74.6 mmol) in N,N-dimethylformamide (125 ml, 1.62 mmol)
was added 1-bromo-3-chloropropane (23.5 g, 149 mmol). After adding 60% NaH
(3.00 g, 75.0 mmol) over 30 minutes at 15.degree.-22.degree. C., the
mixture was stirred for 5 hours at 25.degree.-28.degree. C. The reaction
mixture was poured into iced water (500 ml), extracted with AcOEt (1000
ml.times.3), dried over MgSO.sub.4. The solvent was distilled off, the
residue was chromatographed on silica gel, eluted with CH.sub.2 Cl.sub.2
-CH.sub.2 Cl.sub.2 /MeOH (9/1), and recrystallized from AcOEt to give the
desired compound (24.7 g, 80.5%) as colorless prism crystals.
Melting point: 148.degree.-150.degree. C.
Mass spectrum (EI/DI) m/z: 341 (M.sup.+, base peak).
EXAMPLE 17
(2S,4S)-N-Butyl-1'-[3-(4-hydroxypiperidin-1-yl)propyl]-6-fluoro-2',5'-dioxo
spiro[chroman-4,4'-imidazolidine]-2-carboxamide
A mixture of
(2S,4S)-N-butyl-1'-(3-chloropropyl)-6-fluoro-2',5'-dioxospiro[chroman-4,4'
-imidazolidine]-2-carboxamide (Reference Example 4, 17.0 g, 41.4 mmol),
4-hydroxypiperidine (8.36 g, 82.8 mmol), K.sub.2 CO.sub.3 (7.43 g, 53.8
mmol) and N,N-dimethylformamide (68.0 ml, 880 mmol) was stirred for 5
hours at 80.degree. C. After distilling off the solvent, the residue was
chromatographed on silica gel, eluted with CH.sub.2 Cl.sub.2 /MeOH (9/1),
and evaporated in vacuo to dryness to give amorphous crystals of the
desired compound (18.8 g, 95.4%).
Melting point: 86.degree.-88.degree. C.
IR spectrum (v.sub.max.sup.KBr) cm.sup.-1 : 3400, 1775, 1710, 1660, 1490.
NMR spectrum (DMSO-d.sub.6) .delta. ppm:
______________________________________
0.95 (3H, t, J= 7Hz),
1.22-2.80
(19H, m),
3.17-3.25
(2H, m),
3.46-3.54
(2H, m),
4.58-4.65
(1H, m),
5.14-5.19
(1H, m),
6.98-7.28
(3H, m),
8.31-8.41
(1H, m),
8.75 (1H, s).
______________________________________
Mass spectrum (EI/DI) m/z: 476 (M.sup.+), 114 (base peak).
PRESCRIPTION EXAMPLE 1
Tablets were prepared in a conventional manner with use of following
components.
______________________________________
Hydantoin compound (Example 3)
50 (mg)
Sodium citrate 25
Arginine 10
Polyvinylpyrrolidone 10
Magnesium stearate 5
(Total) 100 mg/tablet
______________________________________
PRESCRIPTION EXAMPLE 2
Tablets were prepared in a prescription similar to that as in Prescription
Example 1, excepting that a product of Example 11 was selected as the
effective ingredient, instead of that of Example 3.
PRESCRIPTION EXAMPLE 3
Tablets were prepared in a prescription similar to that as in Prescription
Example 1, excepting that a product of Example 17 was selected as the
effective ingredient, instead of that of Example 3.
Pharmacological Test Example 1
Acute toxicity
Each of the hydantoin compounds according to the invention was orally given
to female mice to check the acute toxicity. A value of LD.sub.50 was
calculated in accordance with the Litchfield-Wilcoxon method to find it is
more than 5000 mg/kg. This means that the compounds of the invention has
quite low toxicity.
Pharmacological Test Example 2
Inhibition to aldose reductase
An ability for reducing or inhibiting activity of aldose reductase was
checked, in accordance with the method of Kador et al as described in
"Biophys. Chem." Vol. 8, page 81 (1978) and by selecting the hydantoin
derivatives according to the invention, as--Test Compounds--and d-isomer
of 6-fluorospiro[chroman-4,4'-imidazolidine]-2',5'-dione
[--Sorbinil--which is one of exemplary compounds among those described in
Jap. Pat. Sho 53-53653(A), discussed supra], as--Control Compound--.
Results are shown in following Table 1. As apparently seen from the Table,
each of the derivatives according to the invention shows a relatively high
inhibition activity to the aldose reductase.
TABLE 1
______________________________________
Compounds IC.sub.50 (M) (*)
______________________________________
Test Compounds
Example
1 3.8 .times. 10.sup.-8
2 3.0 .times. 10.sup.-7
3 2.2 .times. 10.sup.-8
4 2.6 .times. 10.sup.-8
5 4.4 .times. 10.sup.-8
6 1.3 .times. 10.sup.-8
7 3.7 .times. 10.sup.-8
8 2.2 .times. 10.sup.-7
9 2.4 .times. 10.sup.-7
10 1.5 .times. 10.sup.-7
11 1.9 .times. 10.sup.-6
12 1.5 .times. 10.sup.-7
13 1.9 .times. 10.sup.-7
14 6.5 .times. 10.sup.-7
Control Compound
Sorbinil 2.0 .times. 10.sup.-7
______________________________________
In the Table,
(*) 50% Inhibitory Concentration
PHARMACOLOGICAL TEST EXAMPLE 3
Inhibition of platelet agglutination
A blood was taken from a descending aorta of the rat anesthetized with
ethyl ether. To the blood, 3.8% aqueous sodium citrate was added by a
volume of 1/3 and the resulting solution was centrifuged (1500 rpm) at
4.degree. C. for 10 minutes to obtain a supernatant which was designated
as "PRP (platelet rich plasma)". The remaining residue was centrifuged
(3000 rpm) at 4.degree. C. for 10 minutes to obtain a supernatant which
was designated as "PPP (platelet poor plasma)". A stirrer bar and PRP (267
.mu.l) were inserted in a cell and PPP (more than 300 .mu.l) was charged
in another cell. A transmissivity to PRP and PPP was measured and set as
"0%" for the former case and as "100%" for the latter case.
After a preincubation for 1 minute, a compound to be tested was added by 3
.mu.l and then an agglutination causing substance (collagen or ADP) was
added by 30 .mu.l at a time lapsed of 1 minute from the addition of
testing compound. For a control group, 3 .mu.l of dimethylsulfoxide was
added, instead of the testing compound. A maximum value in transmissivity
change after the addition of agglutination causing substance was
determined and made as a platelet agglutination rate (%). Further, the
inhibition was checked by setting as 100% for a level on each control to
calculate 50% inhibition concentration (IC.sub.50).
Results are shown in following Table 2. As apparently seen therefrom, the
compounds according to the invention show an excellent inhibition to the
platelet agglutination.
TABLE 2
______________________________________
IC.sub.50
Compounds Collagen ADP
______________________________________
Control
Indomethacin 6.8 .times. 10.sup.-5
N.D.
Aspirin 2.1 .times. 10.sup.-4
N.D.
Test compound
Example
3 1.4 .times. 10.sup.-4
N.D.
4 1.8 .times. 10.sup.-4
N.D.
5 2.6 .times. 10.sup.-5
N.D.
6 2.3 .times. 10.sup.-4
N.D.
8 2.5 .times. 10.sup.-4
N.D.
9 6.6 .times. 10.sup.-4
N.D.
10 4.1 .times. 10.sup.-4
7.0 .times. 10.sup.-4
11 8.3 .times. 10.sup.-5
3.7 .times. 10.sup.-4
13 2.4 .times. 10.sup.-4
N.D.
______________________________________
In the Table,
N.D. : not detected.
PHARMACOLOGICAL TEST EXAMPLE 4
Action to the aorta of guinea pig
Hartley guinea pigs (body weight of 300-500 g) were rendered unconscious
fainted by knocking their head and fixed upwardly. A thoracic aorta was
taken out to prepare spiral samples, each having size of about 2.times.25
mm. The sample was suspended in a Magnus tube under a load of about 1 g
and upper end of the sample was connected through a silk thread to a FD
pick-up to record a change in isometric tension.
In the Magnus tube, 10 ml of Krebs-Henseleit solution with following
composition kept at 37.degree. C. was accommodated and 95% O.sub.2 /5%
CO.sub.2 gas was lead therein.
Composition of Krebs-Henseleit solution:
______________________________________
NaCl 118 (mM)
KCl 4.7
CaCl.sub.2 2.55
MgSO.sub.4 1.18
KH.sub.2 PO.sub.4
1.18
NaHCO.sub.3 24.88
Glucose 11.1
______________________________________
Prior to the experiment, the sample in the Magnus tube was left to stand,
as it was, for 60 to 90 minutes and in such period of time, the
Krebs-Henseleit solution was exchanged to fresh one at an interval of 20
to 30 minutes.
After attained in such a state that a recorder shows a stable tensile
force, KCl was added in a amount of 2.5.times.10.sup.-2 M in final
concentration or norepinephrine was added in a amount of 10.sup.-6 g/ml in
final concentration. When the contraction of the sample became constant,
the compound to be tested was gradually added in a amount starting at a
concentration of 10.sup.-8, to 10.sup.6 M to observe the contraction of
the sample. Finally, papaverine was added therein, so as to make its final
concentration of 2.times.10.sup.-5 g/ml, to check and record also the
relaxing reaction or atony caused by the papaverine.
By setting the relaxing rate at stable time after the addition of KCl or
norepinephrine as 100%, a relative value in the reaction for each
concentration was calculated and 50% relaxing (IC.sub.50) was calculated
for data analysis.
Results are shown in following Table 3.
TABLE 3
______________________________________
IC.sub.50 (M)
Compounds KCl contraction
N.E. contraction
______________________________________
Test
Example
1 9.5 .times. 10.sup.-5
2.0 .times. 10.sup.-6
2 >10.sup.-3 >10.sup.-3
3 3.0 .times. 10.sup.-5
8.0 .times. 10.sup.-7
4 >10.sup.-3 >10.sup.-3
5 5.0 .times. 10.sup.-6
3.0 .times. 10.sup.-5
7 >10.sup.-3 >10.sup.-3
8 >10.sup.-3 >10.sup.-3
9 >10.sup.-3 >10.sup.-3
10 1.8 .times. 10.sup.-6
1.0 .times. 10.sup.-4
11 1.9 .times. 10.sup.-6
1.0 .times. 10.sup.-7
12 1.6 .times. 10.sup.-4
3.0 .times. 10.sup.-5
13 6.0 .times. 10.sup.-5
2.0 .times. 10.sup.-5
14 >10.sup.-3 >10.sup.-3
15 8.0 .times. 10.sup.-6
2.0 .times. 10.sup.-6
16 5.9 .times. 10.sup.-5
5.0 .times. 10.sup.-6
17 1.0 .times. 10.sup.-6
3.0 .times. 10.sup.-5
Control
Cinepazide 2.0 .times. 10.sup.-3
1.0 .times. 10.sup.-3
Cinnarizine 2.0 .times. 10.sup.-4
1.0 .times. 10.sup.-4
______________________________________
In the Table,
N.E. : norepinephrine.
PHARMACOLOGICAL TEST EXAMPLE 5
Action to heart of guinea pig
Hartley guinea pigs (body weight of 300-400 g) were rendered unconscious by
knocking their head and fixed upwardly to exenterate their heart. The
heart was inserted in a beaker accommodating a Krebs-Henseleit solution
(see Pharmacological Test Example 4) under 95% O.sub.2 /5% CO.sub.2 gas
atmosphere, to wash out blood adhering thereto and then transferred the
heart to a glass vessel for preparing a sample. The vessel was previously
filled with the Krebs-Henseleit solution and the said mixed gas was
continuously fed therein.
Samples were prepared by separating from a ventricular muscle a right and
left atrium, along an auricloventricular furrow or groove from the
center-line of the right and left auricles.
(a) As to the right atrium sample
The right atrium sample was suspended in a Magnus tube fed 95% O.sub.2 /5%
CO.sub.2 gas and accommodating 10 ml of the Krebs-Henseleit solution kept
at 32.degree..+-.1.degree. C., so that tensile force of the sample became
0.2-0.3 g. A contraction of the sample, due to a compound to be tested,
was recorded through an FD pick-up. Concurrently, pulsations were input to
a measuring unit to count and record number of the pulsations.
(b) As to left atrium sample
The left atrium sample was suspended with a cellfin through both auricles
to a Magnus tube fed 95% O.sub.2 /5% CO.sub.2 gas and accommodating 10 ml
of the Krebs-Henseleit solution kept at 32.degree..+-.1.degree. C., so
that the braking tensile force of the sample became about 0.25 g. The
atrium was driven by contacting it with a platinum bipolar electrode
attached to the cellfin and by stimulating the same with a rectangular
pulse (1 Hz, 1 msec, 10 V). A movement of the sample was recorded by
connecting the sample to a recorder through a silk thread and a FD
pick-up.
In following Table 4, the affects of the compounds are given according to
the invention and control compounds to the right atrium (countering the
pulsations) and to the left atrium (measuring contraction power of heart).
TABLE 4
______________________________________
Pulsation Contraction
Compounds
10.sup.-5 (M)
10.sup.-4 (M)
10.sup.-5 (M)
10.sup.-4 (M)
______________________________________
Test
Example
3 - - - +
4 - + - +
5 - - - +
6 - + - +
8 - + - +
9 - - - +
10 + ++ - -
11 + ++ - +
12 - - - +
15 - - - -
16 - + - -
17 - + + ++
Control
A ++ ++ ++ ++
B ++ ++ - +
______________________________________
In the Table,
A : Propranolol,
B : Ifenprodil,
- : No recognizable influence,
+ : Inhibition of 10-20%, and
++ : Inhibition of more than 20%.
PHARMACOLOGICAL TEST EXAMPLE 6
Influences of compounds according to the invention upon the blood pressure
and cardiac pulsation were checked with use of Hartley guinea pigs, as
experimental animal.
Results are shown in following Table 5.
TABLE 5
______________________________________
Change in Change in
Compound
Dose blood pressure
cardiac pulsation
______________________________________
Control -- -1.1 .+-. 1.5
-0.1 .+-. 0.5
Test
Example
15 3 -2.6 .+-. 1.8
0.0 .+-. 0.0
10 -12.2 .+-. 5.6
-5.4 .+-. 2.9
16 3 -4.0 .+-. 4.0
-1.2 .+-. 1.2
10 -21.3 .+-. 2.4
-4.7 .+-. 4.6
(*)
17 3 -3.0 .+-. 3.0
-1.1 .+-. 1.1
10 -43.8 .+-. 4.9
-48.9 .+-. 2.2
(*) (*)
______________________________________
In the Table,
Dose : mg/kg, i.v.,
Change in blood pressure : %,
Change in cardiac pulsation : %
Control : Physiological saline, and
(*) : There is a significance difference (p < 0.001).
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